Synthesis of Fluorine-Containing Core-2 Tetrasaccharides

Jie Xia; James L. Alderfer; Conrad F. Piskorz; Robert D. Locke; Khushi L. Matta

doi:10.1055/s-2003-40342

LETTER

Synthesis of Fluorine-Containing Core-2 Tetrasaccharides

Jie Xia, James L. Alderfer, Conrad F. Piskorz, Robert D. Locke, Khushi L. Matta*
Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
Fax: +1(716)8453458; e-Mail: khushi.matta@roswellpark.org;

Abstract

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Abstract

Synthesis of core-2 branched tetrasaccharides 1-3, in which a fluorine atom was substituted at the 3 or 4-position of galactose residues is described. Glycosyl imidates 13, and 19 were prepared and used to provide novel glycosyl disaccharide donors 15 and 21, respectively. Coupling of acceptor 7 with glycosyl bromide 6 provides a disaccharide that was further converted into disaccharide acceptor 8. The coupling of acceptor 14 with donor 13, and acceptor 20 with donor 19 provided disaccharides that were converted to disaccharide donors 15 and 21, respectively. Regioselective glycosylation of acceptors 8, and 16 with donors 9, 15, and 21 provided tetrasaccharides 10, 17, and 22 respectively, which were systematically deprotected to targets 1-3.

Key words

tetrasaccharides - galactose residues - core-2 O-linked glycoproteins

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References

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10 Physical data: Compound 1: R_f = 0.5 (i-C₃H₉OH-HOAc-H₂O, 3:1:1); ¹H NMR (D₂O, DQF-COSY and ROESY, 400 MHz): δ = 7.50-7.20 (m, 5 H, ArH), 4.99 (d, 1 H, J _1,2 = 3.4 Hz, H^A-1), 4.72 (d, 1 H, J _gem = 12.6 Hz, PhCH_AO, ABq), 4.61 (dq, 1 H, H^B-3), 4.58 (d, 1 H, J _1,2 = 7.6 Hz, H^B-1), 4.53 (d, 1 H, J _gem = 12.4 Hz, PhCH_BO, ABq), 4.49 (d, 1 H, J _1,2 = 8.6 Hz, H^C-1), 4.48 (d, 1 H, J _1,2 = 7.6 Hz, H^D-1), 4.35 (dd, 1 H, H^A-2), 4.23 (d, 1 H, J = 2.8 Hz, H^A-4), 4.20 (dd, 1 H, H^B-4), 4.15 (dd, 1 H, H^A-5), 4.07 (dd, 1 H, H^A-6b), 4.04 (dd, 1 H, H^A-3), 4.01 (dd, 1 H), 3.94 (d, 1 H, J = 2.7 Hz, H^D-4), 3.90-3.50 (m, 15 H, H^B-2, H^D-2), 2.31 (s, 3 H, Ac), 2.21 (s, 3 H, Ac); ¹³C NMR (D₂O, 100.6 MHz): δ = 175.76 (C=O), 175.52 (C=O), 138.24, 130.07, 129.96, 129.71, 105.12 (d, ³ J _C-F = 11.3 Hz), 104.21, 102.76, 97.62, 94.10 (d, ¹ J _C-F = 183.4 Hz), 79.90, 78.48, 76.65, 76.06, 75.02, 74.96, 73.84, 73.80, 72.27, 70.91, 70.86, 70.77, 70.59 (d, ² J _C-F = 18.6 Hz), 69.97 (d, ² J _C-F = 20.4 Hz), 62.31, 61.94, 61.89, 61.40, 56.39, 49.83, 23.58 (NAc), 23.25 (NAc). ESIMS (negative mode) Calcd for C₃₅H₅₃O₂₀N₂F (m/z)[M = 840]. Found: 839.5[M]^-, 875.5 [M + Cl]^-. Compound 2: ¹ H NMR (D₂O, DQF-COSY, TOCSY and ROESY, 400 MHz): δ = 7.50-7.00 (m, 5 H, ArH), 5.00 (d, 1 H, J _1,2 = 3.2 Hz, H^A-1), 4.87 (dd, 1 H, J = 2.8 Hz, ² J _H-F = 52.0 Hz, H^D-4), 4.73 (d, 1 H, J _gem = 12.3 Hz, PhCH_AO, ABq), 4.59 (d, 1 H, J _1,2 = 7.6 Hz, H^D-1), 4.58 (d, 1 H, J _1,2 = 8.0 Hz, H^C-1), 4.53 (d, 1 H, J _gem = 12.4 Hz, PhCH_BO, ABq), 4.46 (d, 1 H, J _1,2 = 7.8 Hz, H^B-1), 4.34 (dd, 1 H, H^A-2), 4.25 (d, 1 H, J = 2.8 Hz, H^A-4), 4.16 (dd, 1 H, H^A-5), 4.10 (dd, 1 H, H^A-6b), 4.08 (dd, 1 H, H^A-3), 4.02 (dd, 1 H), 3.92-3.80 (m, 6 H, H^C-4), 3.81 (dd, 1 H, H^D-3), 3.80-3.50 (m, 10 H, H^D-2, H^A-6a, H^C-3, H^D-2, H^C-2), 2.31 (s, 3 H, Ac), 2.29 (s, 3 H, Ac); ¹³C NMR (D₂O, 100.6 MHz): δ = 175.80 (C=O), 175.65 (C=O), 129.60, 129.40, 129.30, 105.90, 104.10, 102.85, 97.85, 79.80 (d, ¹ J _C-F = 178.5 Hz), 76.10 (d, ² J _C-F = 50.6 Hz), 73.90, 72.15 (d, ² J _C-F = 50.9 Hz), 71.50, 71.23, 70.25, 70.00, 62.25, 61.23, 56.20, 49.95, 23.50 (NAc), 23.20 (NAc). ¹⁹F NMR (CDCl₃, 376.4 MHz): δ = -172.95 ppm. ESIMS (negative mode) Calcd for C₃₅H₅₃O₂₀N₂F (m/z) [M = 840]. Found: 839.6 [M]^-. Compound 3: R_f = 0.5 (i-C₃H₉OH-HOAc-H₂O, 3:1:1). ¹ H NMR (D₂O, DQF-COSY and ROESY, 400 MHz): δ = 7.50-7.20 (m, 5 H, ArH), 4.99 (d, 1 H, J _1,2 = 3.4 Hz, H^A-1), 4.73 (d, 1 H, J _gem = 12.6 Hz, PhCH_AO, ABq), 4.61 (dq, 1 H, J = 2.8 Hz, J = 9.6 Hz, ² J _H-F = 68.0 Hz, H^D-3), 4.58 (d, 1 H, J _1,2 = 7.6 Hz, H^D-1), 4.55 (d, 1 H, J _1,2 = 8.6 Hz, H^C-1), 4.52 (d, 1 H, J _gem = 12.5 Hz, PhCH_BO), 4.46 (d, 1 H, J _1,2 = 7.6 Hz, H^B-1), 4.33 (dd, 1 H, H^A-2), 4.24 (d, 1 H, J = 2.8 Hz, H^A-4), 4.03 (d, 1 H, J = 3.2 Hz, H^D-4), 4.16 (m, 1 H, H^A-5), 4.07 (dd, 1 H, H^A-6b), 4.04 (dd, 1 H, H^A-3), 4.00 (dd, 1 H, H^C-3), 3.91 (d, 1 H, J = 2.8 Hz, H^B-4), 3.91-3.72 (m, 9 H), 3.64 (m, 2 H, H^C-5, H^B-3), 3.52 (dd, 1 H, H^B-2), 2.31 (s, 3 H, Ac), 2.28 (s, 3 H, Ac); ¹³C NMR (D₂O, 100.6 MHz): δ = 175.77 (C=O), 175.54 (C=O), 138.22, 130.07, 129.95, 129.71, 105.89, 103.41 (d, ³ J _C-F = 12.7 Hz), 102.76, 97.58, 94.08 (d, ¹ J _C-F = 183.9 Hz), 79.81, 78.26, 76.15 (d, ² J _C-F = 17.8Hz), 75.32 (d, ³ J _C-F = 6.8 Hz), 73.79, 73.75, 71.93, 71.05, 70.99, 70.86, 70.73, 70.13, 69.89, 68.15, 67.97, 62.29, 61.99, 61.97, 61.32, 56.43, 49.87, 23.57 (NAc), 23.26 (NAc). ESIMS (negative mode) Calcd for C₃₅H₅₃O₂₀N₂F (m/z) [M = 840]. Found: 839.5 [M]^-, 875.5 [M + Cl]^-